A Cytokine Odyssey: From Interleukin-2 Signaling to Cytokine Therapy for Cancer




Tran, Eric

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T cells are a crucial component of the immune system and play an important role in responses to pathogens, tumours, and transplanted tissues. In many human cancers, elevated numbers of tumour-infiltrating CD8+ killer T cells are associated with favourable outcomes, suggesting that enhancing T-cell responses could provide major therapeutic benefit for cancer patients. Thus, identifying factors that can promote protective T-cell responses is of great clinical importance. The cytokine interleukin-2 (IL-2) is a major inducer of T-cell proliferation and differentiation, and is used clinically to treat melanoma and renal cell carcinoma. The first two chapters of this thesis focus on the biochemical mechanisms by which IL-2 induces T-cell proliferation. By using mutant and chimeric cytokine receptors expressed in lymphocyte cell lines, the interplay between Shc and STAT5, two major mitogenic signaling pathways activated by the IL-2 receptor, are investigated, revealing an essential synergy between the two pathways for optimal lymphocyte proliferation. The third chapter of this thesis describes work done to identify cytokines that promote T-cell responses within the ovarian cancer microenvironment. In human diseases such as HIV/AIDS and cancer, high numbers of “polyfunctional” T cells (i.e., T cells capable of multiple effector functions) are associated with favourable outcomes. Using clinical ovarian cancer samples in a novel ex vivo assay, it was found that the ovarian tumour environment inhibits polyfunctional T-cell responses to varying extents among patients. After surveying a large panel of cytokines, the cytokine combination of IL-2, IL-12, and IL-18 was found to overcome the immunosuppressive environment to potently enhance CD8+ T-cell proliferation and polyfunctionality in all patient samples. The polyfunctional profiles induced by these cytokines are associated with protective immunity in various human conditions. Thus, these findings suggest that given the right signals, T cells can become highly polyfunctional effectors in the ovarian cancer microenvironment, which offers promise for the development of effective T-cell based therapies for this clinically challenging disease.



T cells, melanoma, renal cell carcinoma, cytokines